Neuro(active)steroids actions at the neuromodulatory sigma1 (σ1) receptor: Biochemical and physiological evidences, consequences in neuroprotection

Maurice, Tangui; Grégoire, Catherine; Espallergues, Julie

doi:10.1016/j.pbb.2006.07.009

Cited by 123 publications

(105 citation statements)

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“…Increasing or activating s 1 proteins is expected to counteract ER stress response, whereas decreasing or inactivating them would enhance apoptosis (Hayashi and Su, 2007). Modifying s 1 protein activation using selective activators/agonists therefore mediates a unique pharmacological action on Ca 2 + homeostasis and signal transduction pathways, which has proven to allow an effective neuroprotection against several kinds of insults, including excitotoxicity, oxidative stress, and amyloid toxicity (for reviews, see Maurice et al, 2006;Monnet and Maurice, 2006). Indeed, preliminary experiments showed that, in vitro, the selective s 1 activators PRE-084 and MR-22 attenuate the Ab 25-35 -induced expression of the proapoptotic protein Bax and neuronal death in rat cortical cultures (Marrazzo et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Antiamnesic and Neuroprotective Effects of the Aminotetrahydrofuran Derivative ANAVEX1-41 Against Amyloid β25–35-Induced Toxicity in Mice

Villard

Espallergues

Keller

et al. 2008

Neuropsychopharmacol

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The antiamnesic and neuroprotective activities of the new aminotetrahydrofuran derivative tetrahydro-N,N-dimethyl-5,5-diphenyl-3-furanmethanamine hydrochloride (ANAVEX1-41), a nonselective muscarinic receptor ligand and s 1 protein activator, were examined in mice injected intracerebroventricularly with amyloid b [25][26][27][28][29][30][31][32][33][34][35] ) peptide (9 nmol). Ab 25-35 impaired significantly spontaneous alternation performance, a spatial working memory, and passive avoidance response. When ANAVEX1-41 (1-1000 mg/kg i.p.) was administered 7 days after Ab 25-35 , ie, 20 min before the behavioral tests, it significantly reversed the Ab 25-35 -induced deficits, the most active doses being in the 3-100 mg/kg range. When the compound was preadministered 20 min before Ab 25-35 , ie, 7 days before the tests, it prevented the learning impairments at 30-100 mg/kg. Morphological analysis of corticolimbic structures showed that Ab 25-35 induced a significant cell loss in the CA1 pyramidal cell layer of the hippocampus that was prevented by ANAVEX1-41 (100 mg/kg). Increased number of glial fibrillary acidic protein immunopositive cells in the retrosplenial cortex or throughout the hippocampus revealed an Ab 25-35 -induced inflammation that was prevented by ANAVEX1-41. The drug also prevented the parameters of Ab 25-35 -induced oxidative stress measured in hippocampus extracts, ie, the increases in lipid peroxidation and protein nitration. ANAVEX1-41, however, failed to prevent Ab 25-35 -induced caspase-9 expression. The compound also blocked the Ab 25-35 -induced caspase-3 expression, a marker of apoptosis. Both the muscarinic antagonist scopolamine and the s 1 protein inactivator BD1047 prevented the beneficial effects of ANAVEX1-41 (30 or 100 mg/kg) against Ab 25-35 -induced learning impairments, suggesting that muscarinic and s 1 targets are involved in the drug effect. A synergic effect could indeed account for the very low active doses measured in vivo. These data outline the therapeutic potential of ANAVEX1-41 as a neuroprotective agent in Alzheimer's disease.

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Section: Introductionmentioning

confidence: 99%

Antiamnesic and Neuroprotective Effects of the Aminotetrahydrofuran Derivative ANAVEX1-41 Against Amyloid β25–35-Induced Toxicity in Mice

Villard

Espallergues

Keller

et al. 2008

Neuropsychopharmacol

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“…3A). Such an effect might be due to the fact that those neurosteriods are sigma-1 receptor agonists (Maurice et al, 2006;Dong et al, 2009;Hayashi and Su, 2010) and activation of the sigma-1 receptor resulted in a bipolar modulation of calcium homeostasis in cell and high concentration of agonist could inhibit the free Ca 2+ in cell (Hayashi et al, 2000;Maurice et al, 2006). Since ADAM10 function is induced by free Ca 2+ in cell (Sanderson et al, 2005;Horiuchi et al, 2007), such inhibition could thus inhibit ADAM10-dependent BTC shedding.…”

Section: Discussionmentioning

confidence: 99%

Overexpression of sigma-1 receptor inhibits ADAM10 and ADAM17 mediated shedding in vitro

Liu

Gao

et al. 2012

Protein Cell

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The sigma-1 receptor is a molecular chaperone protein highly enriched in the brain. Recent studies linked it to many diseases, such as drug addition, Alzheimer's disease, stroke, depression, and even cancer. Sigma-1 receptor is enriched in lipid rafts, which are membrane microdomains essential in signaling processes. One of those signaling processes is ADAM17-and ADAM10-dependent ectodomain shedding. By using an alkaline phosphatase tagged substrate reporter system, we have shown that ADAM10-dependent BTC shedding was very sensitive to both membrane lipid component change and sigma-1 receptor agonist DHEAS treatment while ADAM17-dependent HB-EGF shedding was not; and overexpression of sigma-1 receptor diminished ADAM17-and ADAM10-dependent shedding. Our results indicate that sigma-1 receptor plays an important role in modifying the function of transmembrane proteases.

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“…In general, the predominant accumulation of DHEA-Bodipy in the endoplasmic reticulum and mitochondria indicates a specific interaction of DHEA with microsomal and mitochondrial lipids and/or proteins. Besides steroidogenic enzymes, one candidate protein could be the sigma-1 receptor which is highly concentrated on the endoplasmic reticulum (McCann and Su, 1990) and interacts with several neuroactive steroids including DHEA (Maurice et al, 2006). It plays a role in cellular Ca 2+ mobilization and the formation of lipid droplets and lipid microdomains (Maurice et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

“…In PC12 cells, DHEA binds to and activates a Gα coupled receptor that in turn leads to an induction of anti-apoptotic Bcl proteins (Charalampopoulos et al, 2006) and to an activation of Akt kinase (Charalampopoulos et al, 2008). Besides, several other receptors have been proposed as possible DHEA receptors, for example the pregnane X receptor (PXR), estrogen receptor α (ERα) and β and the sigma-1 receptor subtype (Goodwin et al, 2002;Maurice et al, 2006;Webb et al, 2006). To our knowledge, little is known about the intracellular trafficking and localization of DHEA.…”

Section: Introductionmentioning

confidence: 99%

DHEA-Bodipy—A functional fluorescent DHEA analog for live cell imaging

Lemcke

Hönnscheidt

Waschatko

et al. 2010

Molecular and Cellular Endocrinology

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The androgen dehydroepiandrosterone (DHEA) has been reported to protect neuronal cells against dysfunction and apoptosis. Several signaling pathways involved in these effects have been described but little is known about the intracellular trafficking of DHEA. We describe design, synthesis and characterization of DHEA-Bodipy, a novel fluorescent DHEA analog. DHEA-Bodipy proved to be a functional DHEA derivative: DHEA-Bodipy (i) induced estrogen receptor α-mediated gene activation, (ii) protected PC12 rat pheochromocytoma cells against serum deprivation-induced apoptosis, and (iii) induced stress fibers and focal adhesion contacts in SH-SY5Y human neuroblastoma cells. DHEA-Bodipy bound rapidly and specifically to plasma membranes of living PC12 cells. We analyzed metabolism and trafficking of DHEA-Bodipy in human neuroblastoma cells. DHEA-Bodipy is the first functional fluorescent DHEA derivative suitable for live cell imaging of intracellular DHEA transport and localization.

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Neuro(active)steroids actions at the neuromodulatory sigma1 (σ1) receptor: Biochemical and physiological evidences, consequences in neuroprotection

Cited by 123 publications

References 171 publications

Antiamnesic and Neuroprotective Effects of the Aminotetrahydrofuran Derivative ANAVEX1-41 Against Amyloid β25–35-Induced Toxicity in Mice

Antiamnesic and Neuroprotective Effects of the Aminotetrahydrofuran Derivative ANAVEX1-41 Against Amyloid β25–35-Induced Toxicity in Mice

Overexpression of sigma-1 receptor inhibits ADAM10 and ADAM17 mediated shedding in vitro

DHEA-Bodipy—A functional fluorescent DHEA analog for live cell imaging

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